There is great individual variation in the structure and function of the brain. Discovering the determinants of this variation will not only advance our knowledge of normal brain development, but further our understanding of developmental disorders and diseases that affect the brain. The long-term objective of this application is to characterize the differential roles of genes and environment in shaping brain structure and function, to map and identify the genes involved, and to characterize the impact of brain relevant genetic polymorphisms. We shall collect structural images on a genetically informative sample of 700 Australian twins and their non-twin singleton siblings (aged 20-26 yrs) from whom we have previously obtained measures of cognitive functioning, and for whom we have extensive genotyping already available. Using state-of-the-art brain mapping techniques we will establish the genetic architecture and show the trajectory of genetic effects on brain morphometry (Specific Aim 1). In addition to structural MRI, twins and their siblings will participate in diffusion tensor (DTI) (Specific Aim 2) and functional (fMRI) imaging (Specific Aim 3). Our brain mapping techniques will be extended, for the first time, to model genetic and non-genetic influences on white matter micro-structure, and to reveal the genetic topography. The functional imaging study will apply the widely used 'N-back'working memory task, since this is the process most directly linked to individual differences in cognitive ability. We shall assess the extent of genetic mediation and generate the first detailed heritability maps of neuronal activity during working memory. Multivariate genetic modeling of twin/sibling covariance will be used to estimate the relative contributions of genetic factors to co-variance between regional brain structures, areas of working memory-related brain activation, and cognitive ability (Specific Aim 4). Genome-wide linkage and association scans (funded elsewhere) will be used to identify genetic loci that contribute to heritability of brain morphometry and functioning (Specific Aim 5). We will also screen three brain relevant genetic polymorphisms for affects on selected neural phenotypes using sib-pair allelic association analysis (Specific Aim 6). No other imaging study in twins has been designed specifically to use such a QTL-mapping strategy, and this will be at marked cost savings due to the employment of an existing well-genotyped sample. A final aim is to provide a unique and valuable resource base for future investigation (Specific Aim 7). The results of this study will provide fundamental information on genetic mechanisms influencing variation in brain structure and function. This will provide new insights into the origin of individual differences in cognitive functioning and vulnerability to brain disorders.